1. Technical Field
The field of this invention is inhibition of cellular activity related to vascular lesions.
2. Background of The Related Art
In the growth and maintenance of multi-cellular organisms, the organism has had to develop processes to activate or inhibit the proliferation of cells. The organism has developed numerous mechanisms, whereby signals are given to cells, by either intracellular or extracellular messengers. Control of proliferation provides for modeling of organs, maintenance of subsets of leukocytes in hematopoiesis, wound healing and the like. However, in many situations, such as injury or disease states, the response of the organism to the injury or disease may, in fact, be deleterious to the health of the organism.
The vascular response to injury involves an alteration in three fundamental cellular processes; cell growth, cell migration and extracellular matrix production. This vascular response to injury is characteristic of the pathogenesis of various vascular diseases including (but not limited to): atherosclerosis, restenosis after angioplasty, vein bypass graft stenosis, prosthetic graft stenosis, angiogenesis and hypertension. For example, atherosclerotic lesions evolve as a result of vascular smooth muscle migration into the subintimal space, proliferation and the production of abundant extracellular matrix. Similarly, restenosis after angioplasty, vein bypass graft stenosis, prosthetic graft stenosis, angiogenesis and hypertension involve abnormalities in vascular cell growth, migration and matrix composition. The precise mechanisms responsible for alterations in the regulation of these cellular processes are poorly characterized.
Dzau, Hypertension 8, 553-559 (1986) describes the vascular renin-angiotensin pathway. Geisterfer, et al., Circulation Research 62, 749-756 (1988) report that angiotensin II induces hypertrophy of cultured rat aortic smooth muscle cells. Barrett and Benditt, Proc. Natl. Acad. Sci. USA 85, 2810-2814 (1988) describe the expression of platelet-derived growth factor in human atherosclerotic plaques and normal artery wall. Powell, et al., Science 245, 186-188 (1989) report that inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Naftilan, et al., J. Clin. Invest. 83, 1413-1424 (1989) report the induction of platelet-derived growth factor A chain and c-myc gene expression by angiotensin II in cultured rat vascular smooth muscle cells. Sarzani, et al., J. Clin. Invest. 83, 1404-1408 (1989) describe the expression of various growth factors in aorta or normotensive and hypertensive rats. Majesky, et al., J. Clin. Invest., 88, 904-910 (1991) report the production of TGF-.beta..sub.1 during repair of arterial injury. Linder, et al., Circulation Research 68, 106-113 (1991) describe the role of basic fibroblast growth factor in vascular lesion formation. Daemen, et al., Circulation Research, 68, 450-456 (1991) report the role of angiotensin II in inducing smooth muscle cell proliferation in the normal and injured rat arterial wall. Ferns, et al., Science, 253, 1129-1132 (1991) report the inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF, Gibbons, et al., Clin. Research, 38, 287A (1990) report the modulation by transforming growth factor-.beta. of the bifunctional growth response of vascular smooth muscle cells to angiotensin II. Itoh, et al., Biochem. Biophys. Res. Comm., 176, 1601-1609 (1991) report the interaction of atrial natriuretic polypeptide and angiotensin II on protooncogene expression and vascular cell growth.
Simons and Rosenberg, Circ. Res., 70, 835-843 (1992) report that antisense oligonucleotides to non-muscle myosin heavy chain and c-myb suppress smooth muscle cell proliferation in vitro. Speir and Epstein, Circulation, 86, 538-547 (1992) report that antisense to proliferating cell nuclear antigen (PCNA) inhibits smooth muscle cell proliferation in vitro. Rosenberg et al., PCT/US92/05305, January 1993 describes an antisense approach of localized oligonucleotide therapy involving the inhibition of the c-myb or PCNA protein.
The relationship of the expression of cyclins at various phases of the cell synthesis and mitosis cycle are described in The Journal of NIH Research, December 1992, Vol. 4, pp. 55-59. FIG. 1 for example shows the approximate level of Cyclins A, B1, B2, C, D1, D2 and E during G1 (gap 1), synthesis, G2 (gap 2) and mitotic phase of cell proliferation. Williams, et al., The Journal of Biological Chemistry, Vol. 266, No. 12, Apr. 25 (1993), pp. 8871-8880 shows the isolation of cyclin x (p46).
Both of these later two articles and references such as O'Connor, et al., The Journal of Biological Chemistry, Vol. 286, No. 11, April 15, pp. 8298-8308 (1993) elucidate the interaction of various Cyclin dependent kinases such as cdc2 and cdk2 and Cyclins A and B.
Jaskulski et al., Science, Vol. 240, No. 4858, pp. 1544-6 (1988) describes the effects of antisense oligonucleotides on growing Balb/C313 cells. It was shown that the antisense molecule inhibited synthesis and mitosis and sense oligos had no effect. Sala et al., Proc. Natl. Acad. Sci., USA, Vol. 89, No. 21, pp. 10415-9 (November 1992) describes antisense sequences to c-myb gene which inhibit c-myb expression. Kimeki, J. Cell Biochem, Vol. 50, No. 1, pp. 1-9 (1992) describes antisense interruption of C-myc or Cyclin A in vitro. Doyle et al., Antisense Res. Dev., Vol. 1, No. 1 Spring, pp. 11-20 (1991) describes antisense oligonucleotides to Cyclin B in xenopus oocytes. Zindly et al., Biochem Biophys. Res. Commun., Vol. 1897, No. 3, pp. 1144-54 (1992) describes antisense interruption of the production of Cyclin A or Cyclin B in rats. Cyclin A antisense oligonucleotides are also described in Nature, Vol. 354, No. 6351, pp. 314-7 (1991) and Guerria et al., EMBO J., Vol. 10, No. 11, pp. 3343-9 (1991). These references report the effect of Cyclin A or Cyclin B oligos in metaphase I oocytes. Further, antisense studies in xenopus embryos are described in Development, Vol. III, No. 4 pp. 1173-8 (1991) and J. Cell. Biol., Vol. 114, No. 4, pp. 767-72 (1991). Lapidot-Lifson et al., Proc. Natl. Acad. Sci., USA, Vol. 89, No. 2, pp. 579-83 (1992) describe the down regulation of cdc2 with antisense oligonucleotides.